There are three main clinical manifestations of leishmaniasis, which are currently classified as visceral, mucocutaneous, and cutaneous. The clinical form of leishmaniasis is determined by the Leishmania species, geographical location, and immune response of the host. The leishmaniasis diseases are endemic in 97 countries over 4 continents, frequently with one type being more of a threat over the other two in specific regions. It is estimated that more than 12 million people are affected worldwide, with 2 million new cases reported per year (1.5 million CL and 0.5 million VL).
On the other hands Chagas disease, also known as American trypanosomiasis, is a potentially life-threatening illness caused by the protozoan parasite, Trypanosoma cruzi (T. cruzi). It is found mainly in Latin America, where it is mostly transmitted to humans by the faeces of triatomine bugs.
An estimated 10 million people are infected worldwide, mostly in Latin America where Chagas disease is endemic. More than 25 million people are at risk of the disease. It is estimated that in 2008 Chagas disease killed more than 10,000 people.
The classification system divides the genus Leishmania into two sub-genera: Leishmania (L) sensustricto, present in both Old and New World, and Viannia (V), restricted to the New World. Within these two sub-genera, various species complexes have been individualized. Currently, at least twenty different species are recognized as human infectants. The most prevalent species involved in human cases of leishmaniasis are L. (L) donovani, L. (L) infantum, L. (L) mexicana, L. (L) amazonensis, L. (L) tropica, L. (L) major, L. (L) aethiopica, L. (V) braziliensis, L. (V) guyanensis, L. (V) panamensis and L. (V) peruviana. Each of these species is found in different locations worldwide and is responsible for causing different types of leishmaniasis.
Visceral leishmaniasis is the most pathogenic of the three types. It is caused by species of L. (L) donovani complex and L. (L) infantum. The common symptoms include irregular fever, weight loss, swelling of the spleen and liver and anemia. If left untreated, visceral leishmaniasis will lead to death. Endemic L. (L) infantum visceral leishmaniasis affects mainly children and L. (L) donovani VL affects people of any age group living in urban and rural areas. The onset of this type is usually abrupt, but symptoms may appear beginning 3 weeks to 2 years after exposure. With epidemic visceral leishmaniasis, all age groups are equally susceptible. With this type, males are also more likely to be infected than females at a ratio of 4:3. At this time, there is little understanding of the mechanisms by which apparent selectivity of hosts and effects are carried out.
Most research to treat leishmaniasis is focused on the development of improved chemotherapies because current drugs are unsatisfactory. Pentavalent antimonials, such as meglumine antimoniate and sodium stibogluconate are the most used anti-leishmanial drugs. While they can be therapeutic, they have unsatisfactory side effects such as systemic toxicity (cardiac, renal and hepatic), chemical pancreatitis, decreases in RBCs (Red Blood Cell Count), WBCs (White Blood Cell Count) and platelet counts and reversible peripheral neuropathy. Additionally, these drugs require prolonged treatment. The treatment with antimonials includes repeated [daily intramuscular or intravenous] injections for 20-28 days, requiring medical supervision. It is recommended that 20 mg/kg body weight be injected daily over that period of time. In addition to these drawbacks, Leishmania parasites are also becoming increasingly resistant to these treatments.
Amphotericin B is a secondary treatment used for leishmaniasis, especially when antimonial treatment has not been effective. This treatment is parenteral in nature and also highly toxic. It was found, however, that a total dose of 15 mg/kg body weight is 100% effective and a dose of 5-10 mg/kg is 90% effective against the Indian visceral disease. A liposomal formulation reduces the toxicity, but at a higher cost.
Other currently used drugs include the alkyl-glycero-phosphocholine, miltefosine, pentamidine and ketoconazole. Miltefosine is the first oral medication approved against leishmaniasis. Miltefosine commonly induces gastrointestinal side-effects such as anorexia, nausea, vomiting (38%) and diarrhea (20%). Most episodes are brief and resolve as treatment is continued. Occasionally, the side-effects can be severe and require interruption of treatment. Skin allergy, elevated hepatic transaminase concentrations and, rarely, renal insufficiency may be observed. Miltefosine should be taken after meals, and, if multiple doses are to be taken, they should be divided. Miltefosine is potentially teratogenic and should not be used by pregnant women or women with child-bearing potential for whom adequate contraception cannot be assured for the duration of treatment and for 3 months afterwards.
Ketokonazole have variable efficacy in leishmaniasis treatment. Pentamidine is given intramuscularly or, preferably, by intravenous infusion. Severe adverse effects—diabetes mellitus, severe hypoglycaemia, shock, myocarditis and renal toxicity—limit its use.
New drugs such as paromomycin (aminosidine), an aminoglycoside antibiotic, usually administered intramuscularly, are under study. The 15 mg/kg sulfate is equivalent to 11 mg/kg of base, and the 20 mg/kg sulfate is equivalent to 15 mg/kg of base. Mild pain at the injection site is the commonest adverse event (55%). Reversible ototoxicity occurs in 2% of patients. Renal toxicity is rare. Some patients may develop hepatotoxicity, indicated by raised hepatic enzyme concentrations; tetany has also been reported.
Quaternary ammonium compounds such as octadecyltrimethyl ammonium bromide and dodecyltrimethyl ammonium bromide have also been reported to inhibit the growth of L. major promastigotes. The use of alkyl quaternary ammonium compounds including certain choline analogs for treating or preventing fungal and trypanosomal (e.g., Leishmaniasis) infections is also known.
The compounds seem to inhibit or perturb choline transport into the parasites, thus inhibiting parasites growth. Other quaternary ammonium salts that are known antibacterials, such as methylbenzethonium chloride, benzethonium chloride, cetalkonium chloride, benzalkonium chloride, and cetrimonium bromide have been used in combination with other drugs such as paromomycin and meglumine antimoniate; as a well as benzethonium chloride, in combination with other drugs such as hexadecyl-phosphorylcholine.
Chagas disease can be treated with either benznidazole or nifurtimox. Both medicines are almost 100% effective in curing the disease if given soon after infection at the onset of the acute phase. However, the efficacy of both diminishes the longer a person has been infected. Benznidazole and nifurtimox should not be taken by pregnant women or by people with kidney or liver failure. Nifurtimox is also contraindicated for people with a background of neurological or psychiatric disorders.
Multiple metabolic pathways and specific molecular targets have been studied in trypanosomatid parasites. Membrane lipid biosynthesis pathways are a viable target for anti-trypanosomal compounds since phospholipids have an important role in the cell biology of the parasite and membrane lipid composition differs significantly when compared to mammals.